Bridging the Gap: Pregnancy—And Lactation—Associated Osteoporosis

Early diagnosis of pregnancy- and lactation-associated osteoporosis (PLO) is mandatory for a good outcome. Standard care is not a matter of conventional guidelines, rather it requires an individualized strategy while true overall incidence and pathogeny remain open issues. This is a narrative review based on full-length English articles, published between January 2021 and March 2023 and accessed via PubMed (no traumatic fractures or secondary osteoporosis are included). Our case-sample-based analysis included 836 females with PLO (the largest cohort based on published cases so far) through 12 studies and 24 single case reports. Except for one survey, these involved retrospective cohorts of small size (6–10 females/study) to medium size (23–47 women/study), and large cohorts with >50 subjects per study (a maximum of 379). Age of diagnosis: from 24 to 40 years for case reports (most subjects being over 30 and primigravida), while original studies indicated an average age between 31 and 34.18 years. Type of fractures underlined a most frequent vertebral phenotype (a mean of 2 to 5.8 vertebral fractures per patient) versus a most severe non-vertebral phenotype (hip and femoral neck fractures mostly requiring surgery). Potential contributors varied: smoking (1/3–1/2 of subjects), family history of osteoporosis (1/3), heparin and glucocorticoid use in pregnancy, low body mass index (majority of cases), hypovitaminosis D; and (with a low level of statistical significance) anti-psychotic medication, gestational diabetes, lupus, thrombophilia, anemia, in vitro fertilization (1/3 in one study), twin pregnancy, tocolysis with MgSO4, and postpartum thyroiditis. Most remarkably, up to 50% of PLO patients harbor mutations of LRP5, WNT1, and COL1A1/A2 (more damaged form with potential benefits from osteoanabolic drugs); gene testing might become the new norm in PLO. The low index of clinical suspicion should be supported by performing magnetic resonance imaging (gold standard in pregnancy) with DXA (in lactation). Low bone mineral density is expected (Z-score varying from −2.2 SD to −4 SD, unless normal which does not exclude PLO). Bone turnover markers might be useful in individuals with normal DXA, in pregnancy when DXA cannot be performed, and in following the response to anti-osteoporosis drugs. Alternatively, microarchitecture damage might be reflected by DXA-trabecular bone score and high-resolution peripheral quantitative computed tomography. Specific medical interventions are currently focused on teriparatide (TPT) use (3 studies; n = 99 females treated with TPT and an additional subgroup of 18 patients from the gene-analysis-based study, thus a total of 117 females) which seems to be the therapy of choice as reflected by these new data: 6–24 months, 20 µg/day, no sequential therapy needed; case selection based on high fracture risk is necessary). The first case using romosozumab was reported in 2022. PAO/LAO remains a challenging condition which is a battle for the wellbeing of two individuals, on one hand, considering maternal-fetal outcomes and taking care of the offspring, but it is a battle for a multidisciplinary team, on the other hand, since a standardized approach is lacking.

manually checked each of them, excluded the duplicates and selected 12 studies and 24 case reports (a total of n = 836 females with PAO/LAO) according to the inclusion/exclusion criteria. We considered different areas of interest including fracture sites, pregnancy versus lactation onset, original studies versus single case reports, various elements of management from surgery to specific medication against osteoporosis, etc.

Results: PAO and LOA
According to our methods, we identified the following 12 original studies. (Table 1)  Toba 2022 [41] retrospective n = 837,347 females who had 2-year history of obstetric admission rate of fractures within first 2 y after birth: 4.5/10,000 pregnancies (n′ = 379) 7.5%: recommendation for stopping breastfeeding or anti-osteoporotic drugs

Cohort-Based Analysis
A nationwide study reported in the Japanese Diagnosis Procedure Combination database included 837,347 females who had 2-year history of obstetric admission (between 2010 and 2014); the rate of fractures within this period of time was 4.5 per 10,000 pregnancies; 6.7% of the cohort had bone imaging or a BTM assay; 7.5% of them had a medication recommendation (considered in this study to be cessation of breastfeeding or administration of specific drugs against osteoporosis). The authors identified potential risk factors for LAO: maternal age older than 40 years, smoking, glucocorticoid exposure, and a high Charlson Comorbidity Index score (of at least 1) [41].
We identified 3 studies on TPT with different perspectives (a total of 99 females treated with TPT in these 3 cohorts). A study including 47 women with PAO/LAO (enrolled between 2006 and 2018) treated with TPT (20 µg/day, 24 months plus VD, followed by stopping any medication against osteoporosis while resuming normal menstruation or taking estrogen-progestin contraceptives) showed an average number of fractures of 4, as confirmed by plane X-ray or MRI. These included incidental fractures under therapy (4/47) that were confirmed within first 3-5 months of TPT (2/4), or after the first 6 months of TPT (2/4). DXA showed statistically significant BMD increases (p < 0.001) of 30.1% (lumbar spine), 11.7% (femoral neck), and 12.2% (hip) with similar values after 1 year since stopping TPT [40].
The third TPT study included 67 women with PAO/LAO (between 2007 and 2017), of whom 43 were assessed at DXA annually for 3 years; among these, 33 females received TPT (a median of 12 months, mean age of 31) followed by anti-resorptive medication (sequential group; N1 = 13, median of 18 months) or drug discontinuation (N2 = 20). Similar lumbar and hip BMD increases were registered after each of the 3 years regardless of the subgroup (N1 versus N2), thus suggesting there is no need for a sequential approach [46].
A single clinical study (between 2010 and 2019) on 10 females (median age of 30 years) showed that 1/10 of them had a twin pregnancy, 4/10 were smokers, and fractureassociated pain was identified at a median of 4 weeks after birth; 7/10 of the subjects had VFs; the mean lumbar T-score was −2.91 SD. Management included stopping breastfeeding (8/10) with VD and calcium supplementation. Pain control was achieved after a mean of 2.4 months (the longest period was in females who continued lactation up to 4 months). One patient required vertebroplasty; four out of the eight females without breastfeeding used BPs, apparently with similar outcomes as seen in BP-negative patients [42].
In addition to a new case report of PAO, Miles et al. introduced a TriNetX-based study (n = 135 patients with LAO); the authors took into consideration patients between 10 and 50 years who suffered an osteoporotic fracture within first year after delivery; 44% of the subjects had lumbosacral fractures. Therapy included 10 types of drugs (n = 70 patients with available data) at equal rates (of 7%): DEN, TPT, ZOL, pamidronate, ibandronate, etidronate, alendronate, risendronate, calcitonin, cinacalcet [44].
One retrospective study (between 2007 and 2012) compared subjects with PAO (n = 7 primiparous with VFs in 6/7 and TOH in 1/7) during lactation with healthy control females who were breastfeeding; trabecular density as assessed by high-resolution peripheral quantitative computed tomography (CT) was 34% lower than in controls (p < 0.01), and the cortical thickness was 22% lower (p = 0.01), thus proving that both trabecular and cortical microarchitecture are damaged through PAO [47].
A German multicenter study on 42 individuals with PAO/LAO (between 2013 and 2019) identified genetic variants concerning LRP5, WNT1, and COL1A1/A2 genes in 21/42 fe- males. The subgroup harboring genetic anomalies had a higher number of VFs (4.8 versus 3.3, p = 0.02), while their Z-score was lower (p = 0.002) and trabecular and cortical thickness was statistically significantly reduced according to HRPQCT. Among these females, 43% (n = 18) received TPT, with a +3.7.7% bone mass increase after 3 years, thus suggesting that females with PAO carrying genetic variants might be candidates for osteoanabolic drugs [48].
One imaging (MRI-based) retrospective study on females (n = 1260) older than 15 years and younger than 40 years analyzed compression VFs and identified 6 females with PAO-/LAO-associated VFs, representing 0.5% of the entire cohort. Similar features are found in VFs regardless of the underlying history of PAO/LAO. In this particular instance, the mean age of the subjects was 31 years (between 25 and 37), the average number of VFs was 5.6 (between 1 and 11), and a DXA correspondent with low BMD was reported in 4 out of the 6 subjects [49].
Overall, the mentioned studies display great variation in patient approaches from the perspectives of clinical and imaging evaluation. The patients identified with osteoporosis in pregnancy were typically in their 30 s and were admitted for local pain and functional impotence. Most reports of imaging scans are related to the use of DXA after delivery.

Transient Osteoporosis of the Hip (TOH)
TOH, a self-limited condition of late pregnancy or the early postpartum period (but rare reports of TOH in children and middle-aged men are also found) of mostly unknown cause, represents a major cause of dramatic hip pain during this time. MRI is the diagnostic method of choice during pregnancy and, once confirmed, it becomes a comorbidity that should be taken into consideration when deciding the timing and type of delivery (some consider TOH as an indication of emergency cesarean) [38,[50][51][52][53][54]. For example, one case of TOH reported a bilateral femoral neck fracture during week 34 of gestation; emergency caesarean was provided to the 24-year-old patient followed by bilateral closed reduction and internal fixation (dynamic hip screws), followed by hip replacement on the left side due to fixation failure. Of note, postpartum DXA assessment showed a Z-score of −0.7, while BMI at the moment of fracture was 32.8 kg/sqm (a value of BMI that is uncommon in PAO) [55].
The true incidence of TOH remains less understood, most cases being unilateral, while bilateral involvement is less frequently reported [55]. The risk factors panel overlaps with general data on PAO/LAO, yet this is still a matter of debate. For instance, one female was recently identified with displaced femoral neck fracture in week 35 of gestation, with reports noting that she had a history of thrombophilia (factor V Leiden) and anemia [56].
TOH-associated pain brings a rather low index of suspicion, and no standard management is recommended; a conservative approach in late pregnancy should be firstly advised after careful consideration by a multidisciplinary team. Postpartum spontaneous recovery is reported within an average of 6 weeks [38,50,51].
A single-center study involving 34 females (mean age of 34.18 y) with PAO (n = 17) and LOA (n = 17) and unilateral or bilateral (25%) TOH were confirmed via MRI; their profile showed the following potential contributors to TOH: maternal (family) history of osteoporosis in 29% of cases, smoker rate of 47%, IVF (in vitro fertilization) in 32% of cases. Similar maternal outcomes were registered regardless of the type of delivery (cesarean or vaginal) [38] (Table 2).  While the vertebral phenotype is the most frequent, the most severe presentation involves TOH. In this particular situation, DXA evaluation might not reflect the severity of the condition.

Stress Sacral Fractures (SSF)
In addition to VFs, non-VF sites also include pelvic fractures [63]. Moreover, SSTs, alternatively named sacral insufficiency fractures or fatigue fractures, are commonly found in primary menopausal osteoporosis, but exceptions are reported, as seen in young females diagnosed with PAO/LAO [39,69,70].
A study from 2023 (n = 29,291 pregnant females with a delivery registered between 2016 and 2021) identified 0.078% of these females (n = 23, 74% of them were primigravidae) as suffering of SSF-associated lower back and pelvic pain in pregnancy (with MRI confirmation); 74% of them had postpartum pain persistence; one-third of this PAO cohort had 25-hydroxyvitamin D (25OHD) levels less than 20 ng/mL [39].
In 2021, a new case report of a 39-year-old female introduced SSF as part of the PAO panel. The authors reviewed the literature with regard to SST-PAO/LAO and found that 65% of cases are identified during lactation, no particular risk factors have been confirmed, and lumbar radiculopathy is diagnosed in 17.6% of subjects. As an investigation tool, MRI scan is the primary choice, while DXA might not be particularly helpful since 70% of the females do not present with low BMD. Most cases have a favorable outcome with adequately reduced physical activity [71]. Similarly, another report showed that PAO/LAO-associated VFs might not be associated with postpartum DXA anomalies [72]. SSF in pregnancy was also reported due to excessive weight gain when limited outdoor activities were recommended during the COVID-19 pandemic [73]. However, prior studies have shown that PAO/LAO is exceptionally described in obese patients, which might potentially explain higher postpartum DXA-BMD [74,75].
Of note, SSF belong to a larger panel of conditions and PAO/LAO might have only a small epidemiologic impact. Awareness of this context is therefore important.

Case Reports of LAO
The case-sample analysis revealed some interesting scenarios according to publications from within latest 29 months. A 34-year-old female was treated with TPT followed by ZOL (in a recent case published in 2023) with a good outcome registered by central DXA and high-resolution peripheral quantitative CT scans, but reported values remained lower than similar controls at 40 months after delivery. Genetic tests (considering the traditional panel for monogenic osteoporosis) were negative, thus being suggestive of a polygenic involvement in the pathogenic loop of osteoporosis [58].
A 29-year-old subject experienced lower thoracic and lumbar pain with lower limb irradiation that was more intense when walking and decreased when lying down, 6 months after her delivery. MRI scan confirmed lumbar L1-2 kyphosis, scoliosis, and multiple VFs while central DXA revealed a Z-score less than −4 SD; VD levels were adequate as reflected by serum 25OHD of 28 ng/mL. LAO, as indicated by the clinical and imaging assessment, was treated by stopping lactation (via bromocriptine use), oral cholecalciferol (6000 UI/day), calcium, and alendronate (70 mg/week). Check-up at 4 months showed a good outcome [59].
The first case of PAO/LAO treated with ROM was reported in 2022, for a 34-yearold (primigravida) Japanese female experiencing low back pain 4 weeks after birth while she was breastfeeding. Low BMD-DXA (lowest Z-score of −2.2 at the lumbar spine) and multiple VFs at lumbar L1-L4 confirmed LAO. She started TPT (for 4 months, 56.4 µg/week, twice a week) which was stopped because of persistent nausea, but also inefficiency (an incidental VF at T11 was detected); she was therefore offered ROM for 1 year without new fractures (BMD increases of 23.6%, 6.2%, and 11.2% at lumbar spine, femoral neck, and hip) [60].
The subject was a 34-year-old female who experienced back pain unresponsive to usual analgesics, which turned out to be LAO-associated multiple VFs (at thoracic and lumbar level) requiring her to stop lactation and start anti-osteoporosis drugs. Potential contributors, as suggested by Ferreira et al. [61], are systemic lupus and positive anti-phospholipid syndrome [61]. Novel contributors might be part of a polygenic spectrum, as in the case of a 35-year-old woman who experienced multiple VFs two months after her second birth. Her lowest DXA Z-score was of −3.5 SD, and she was identified as carrying a WNT1 mutation (heterozygote missense -p.Leu370Val). She received TPT for 24 months that increased lumbar BMD by 14.6%, femoral neck BMD by 8.3%, and hip BMD-DXA by 4.9% [62]. Another risk factor for LAO was suggested in the analysis by Lio et al. [64] with respect to long-term tocolysis with MgSO 4 and associated glucocorticoid exposure (also with a new case report). This procedure (that allows fetal lung development) increases urinary calcium loss and might cause hypocalcemia due to magnesium-induced parathormone (PTH) suppression, thus potentially causing reduced BMD [64]. Han et al. [65] proposed a new pathogenic element for LAO: postpartum thyroiditis associated with thyroid hormone flare-up. A first such case was reported in 2021: a 25-year-old female was diagnosed with multiple VFs after delivering her first child. She stopped lactation, daily calcitriol (0.5 µg) and calcium (1 g) were added to ibandronate 3 mg/3 month during rehabilitation, and thyroid profile progressively improved [65]. Another 33-year-old female was confirmed with LAO (VFs at lumbar L1 and L4 levels) after a pregnancy requiring heparin use; DEN (60 mg every 6 months, subcutaneous) was offered for 18 months with a DXA-BMD increase of +32.2% (lumbar), +13% (femoral neck), +11.5% (total hip); she later had a second pregnancy and her BMD value, while being decreased, never reached the nadir experienced previously [66].

Case Reports Requiring Surgery
While VFs are more frequent than hip involvement, vertebroplasty is less reported than surgery for hip and femoral neck fractures due to their severity [42]. For instance, a 38-year-old female had an apparently spontaneous femoral neck fracture as part of PAO in week 28 of her gestation; she presented a sub-capital femoral neck fracture that required closed reduction and internal fixation in a surgical procedure that went well. After cesarean (week 38), she was followed for 2 more years after fracture consolidation with a good outcome [76].
Another 37-year-old woman suffered a hip fracture (gestation week 38); MRI confirmed this particular type of TOH. After emergency cesarean was performed and positron emission tomography-computed tomography (PET-CT) scanning excluded other causes of fractures, total hip arthroplasty was performed. Of note, 25OHD was low (25 nmol/L, normal levels between 50 and 160 nmol/L), and she further continued with VD supplementation, ZOL, and no breastfeeding [57].
A primigravida in her 30 s was no longer able to walk soon after delivery by cesarean (week 37) due to persistent hip pain (since week 28 of pregnancy). She had a history of schizophrenia and associated drug-induced hyperprolactinemia and was confirmed with gestational diabetes mellitus. X-ray confirmed bilateral sub-capital femoral neck fracture requiring total hip replacement (right) and internal fixation (left) (one-time postpartum surgery) as part of TOH management. Her 25OHD was normal, and her Z-score (according to central DXA) was low, less than −3.7 SD, and thus she was offered BP for 6 months with a good clinical outcome [23]. The earliest LAO onset was reported within the 6 th day after birth in a 24-year-old female who was confirmed with displaced sub-capital femoral neck fracture (as a form of TOH) that required hip replacement [68]. Having surgery within the postpartum period, the ability to take care of the newborn might be impaired and the recommendation of continuing breastfeeding is registered in most cases.
Due to the current level of statistical evidence, the different scenarios we have mentioned according to the case reports might be taken into consideration for personalized decisions until more data become available worldwide. These cases also raise the suggestion of novel potential contributors to bone loss and fractures in young females that have been reported in other forms of osteoporosis, including certain chronic autoimmune or inflammatory conditions or drugs.
Concerning the types of assessment among the mentioned studies, we found that one study [48] performed a genetic analysis (in addition to two of the case reports [58,62]), another cohort started from a large series of MRI scans [49], and two other studies (and a case report) used high-resolution peripheral quantitative CT [47,48,58]. Two studies analyzed the fracture rate within one year, respectively 2 years since delivery in larger cohorts [41,44]. Remarkably, a maximum of 837,347 women were screened in one of those [41], while another different trial checked for SSFs among 29,291 individuals [39].
Regarding the ages of the patients, in case reports these varied from 24 to 40 years (most subjects being within their third decade of life), while original studies indicated an average age between 31 and 34.18 years [38,49]. These data are consistent with prior observations [74].
Of note, we did not restrict our case-sample-based study to a systematic review, since various parameters were differently reported and we opted for a broader perspective. The current work follows a systematic review by Qian et al. [74] from 2021 that included 65 articles (n = 338 females with PAO/LAO, but final analysis was performed on 173-191 documented reports depending on end point; the number of cases per article varying from 1 to 107) [74]. All these articles were published between 1990 and 2020. Therefore, we chose to initiate our analysis using reported data from 2021, also taking into consideration the reality of the COVID-19 pandemic which was in its first waves during 2020 (thus necessitating a slightly different methodology). Qian et al. [74] reported the following interesting data: the average age at PAO/LAO diagnosis was 35.7 years (from 19 to 47 years), 91.5% of patients experienced fracture-associated local pain within the last 3-month period of gestation and the first 3-month period of lactation (the earliest from 5 months of pregnancy and the latest to 9 months of lactation) [74].
From our perspective, bridging the gap with respect to PAO/LAO involves a few clusters of elements that are still to some extent open issues under the remarkable umbrella of low statistical evidence due to the rarity of the condition. These elements are discussed below.

Gap 1: The Time Frame of Defining LAO
As mentioned, typically the diagnoss of PAO/LAO is established by the end of the pregnancy and beginingg of breastfeeding, usually in a 3-month period of each (some consider LAO as being associated with the first year after giving birth) [77][78][79][80]. It is debatable whether a recent history of an obstetric event (within 2 years) might be a part of LAO. Toba et al. [41] identified a fracture rate of 4.5/10,000 pregnancies, which was correlated with contributors including smoking and glucocorticoid exposure within a 24-month interval [41]. We raise the question of whether a recent history of pregnancy and lactation, but not a current status of breastfeeding, might actually underline LAO. Clearly defining lactation status (and even resumption of menses) should be part of LAO diagnosis/differential diagnosis, because a fracture during the bone-recovery phase might not be LAO but may be related to a traumatic event (with less clear data collected during anamnesis) causing a fracture or a secondary form of osteoporosis in young adults. Of note, the majority of maternal calcium loss via milk takes place within the first weeks after delivery. Adjustment of cortical bone in order to allow rapid calcium release from trabecular bone in pregnancy and lactation, despite being physiological, varies greatly from one skeletal site to another and from one person to another [81][82][83].

Gap 2: Re-Shaping the Concept and the Approach of PAO/LOA
The true epidemiology of PAO/LAO remains unknown. Pre-conception prediction of PAO/LAO is impossible [84,85]. A first pregnancy complicated with this type of osteoporosis might not be followed by a second one with the same complications (despite the patient most probably displaying the same list of potential risk factors); on the other hand, experiencing PAO (as a first-time event) during the second pregnancy is described in less than 10-30% of cases [62,66,74].
PAO and LAO are difficult to distinguish from one another; some patients present with fracture-associated pain after gestation, but the actual discomfort started late during pregnancy and remained unexplored. PAO was clearly identified in other females during pregnancy, which persisted according to local examinations or assessments of skeletal anomalies in the postpartum period regardless of VD and calcium replacement (thus PAO might continue as LAO). It is debatable which pathogenic components are more important in inducing fractures in pregnancy or during lactation, whether they are two faces of the same clinical entity with unknown triggers or are actually distinct conditions. Moreover, there is a low index of suspicion regarding TOH as a specific subgroup of PAO/LAO with dramatic severity. Therefore, it is important to obtain adequate diagnosis considering a multitude of differential diagnostics starting from the associated local and general pain.

Gap 3: Vertebral versus Non-Vertebral Phenotype of PAO/LAO
While most cases of PAO/LAO include VFs, non-vertebral involvement includes TOH [38,55,56]. Furthermore, SSFs should be mentioned in this context, as revealed by a large study on SSFs with different causes; a rate of 0.078% is due to this entity, mostly seen in primigravidae [39]. Previous data reported by Qian et al. [74] found that one-third of all fractures were located at thoracic T12 and lumbar L1 and L2 vertebra with an average number of fractures of 4.4 [74]. Our analysis identified an average number of VFs of 4 in 2 studies [40,45] compared with 5.6 in another study [49]. Patients referred for TPT therapy suffered from more VFs than those who were managed with VD and calcium (4 versus 2.5) [42], while the subgroup with genetic variant carriers had higher VFs when compared with the non-genetic subgroup (3.3 versus 4.8) [48]. Rates of incidental fractures after diagnosis of PAO/LAO were established and patients starting anti-osteoporotic drugs were also reported [40,60]. The rate of new VFs under TPT varied from 0% to 7.8% [40,45]. However, this is difficult to attribute to drug inefficiency or to overestimated early effects of those drugs.
Despite not being a matter of general consensus, malleolar fracture might be part of LAO. For instance, this may apply in the case of a 31-year-old female experiencing such a fracture within the first 3 months since starting breastfeeding; the lesion required open reduction and internal fixation (which was removed one year later while she remained under BPs) [67].
Another site yet to be taken into consideration is the tibia [86]. A 25-year-old female was admitted postpartum for bilateral knee pain that turned out to be a stress fracture of the proximal tibia. The event was triggered by restarting physical activity, which should be done carefully [87]. Miles et al. [44] included foot, toe, and ankle fractures in their study, that are debatable in terms of their LAO status; indeed, however, any fracture during lactation should be suspected as being LAO [44]. Finally, we conclude that a general multidisciplinary approach should include assessment of vertebral or non-vertebral phenotype in PAO/LAO, the first being the most frequent, the second one associated with the most dramatic impact in cases with hip and femoral neck fractures; uncertainty remains for all the other sites (if they are actually part of the same condition).

Gap 4: The Playlist of PAO/LAO Contributors
Obesity is hardly found as risk factor for PAO/LAO due to the fact that increased BMI helps the bone's load-bearing function and thus bone formation [55,74]. More than 70% of females who experience the condition do not have abnormally high BMI [71]. Low pre-pregnancy BMI might induce a lower BMD after birth [88].
Siva et al. [23] reported the use of anti-psychotic medication, hyperprolactinemia, and gestational diabetes mellitus as contributors to bone loss [23]. Of general note, the panel of gestational diabetes-associated maternal-fetal complications is extremely heterogeneous, and a potential negative skeletal impact might be expected [89][90][91][92].
Ferreira et al. [61] showed that lupus is a potential contributor to PAO/LAO [61]. A retrospective study from 2022 including 30 patients with systemic lupus erythematosus in pregnancy (versus 31 non-pregnant controls suffering the same condition) confirmed postpartum BMD loss compared with controls (p = 0.048); the multivariate regression identified that low pre-conception BMI, long-term glucocorticoid exposure, and maternal age at birth were associated with hip BMD loss [88]. Furthermore, thrombophilia (factor V Leiden mutant) and anemia might contribute (single case-report level) to PAO, adding bone issues to a large panel of complications such as increased risk of gestational thrombotic events [56,93].
Toussia-Cohen et al. [38] showed that one-third of females with the condition had family history of osteoporosis, while one-third of them had received an IVF procedure, which seems to be a new player among the contributors, but with an insufficient level of statistical evidence to back up this association [38]. Moreover, half of the women were smokers, smoking being a traditional risk factor for bone loss and increased fracture risk at any age [38,94,95]. Two further studies also confirmed the association with smoker status [41,42]. Aytar et al. [42] reported the condition in twin pregnancy, albeit with an unknown level of statistically relevant correlation [42]. Tocolysis with MgSO4 might ag-gravate LAO [64], similar to heparin therapy in pregnancy [66]. A first case of postpartum thyroiditis-associated transitory thyrotoxicosis was reported in association with LAO [65], noting the general negative impact of excessive thyroid hormones on bone loss as seen in patients with long-term levothyroxine-suppressive therapy following surgery for differentiated thyroid carcinoma [96]. Hypovitaminosis D was also identified in up to one-third of the LAO population in one study [39,57].
All these confirmed previous data (before 2021) showed that the risk of PAO/LOA increases with advanced maternal age (more than half being older than 30 years) and reduced BMI (only exceptional cases are registered in obese patients). One-third of subjects were exposed to anticoagulation medication in pregnancy, one-third of them had positive family history of osteoporosis, while one-fifth were current or past smokers (apparently a lower proportion than in the studies we have identified and mentioned published since 2021) [38,74].
We appreciate genetic testing as the most innovative approach to understanding PAO/LAO pathogenic pathways [58,62]. Particularly, the study by Butscheidt et al. [48] showed that half of these females harbor mutations of LRP5, WNT1, and COL1A1/A2 that are associated with a more damaged bone profile than non-genetic forms, thus making them candidates for osteoanabolic drugs [48]. Probably, testing these genes, especially LRP5, could become the new norm for approaching PAO/LAO in the future.
As previously observed by Qian et al. [74], limited data are provided to determine whether vaginal delivery or cesarean is associatied with higher risk of developing LAO, which remains an open question [74].
Furthermore, the increasing prevalence of bariatric surgery in young females of reproductive age might impair bone status in pregnancy and lactation. Generally, a 1-2-year gap between metabolic surgery and pregnancy is recommended [97,98]. We question if bariatric/metabolic surgery should be listed as a potential contributor to PAO/LAO, noting the increasing numbers of young patients benefiting from this procedure (we mention a first published case from 2019) [99], also recognizing that bariatric surgery increases the risk of fracture outside pregnancy, due to malabsorption, VD deficiency, reduced bone formation caused by lower body weight, gut-derivate calciotropic hormones anomalies, etc. [100,101].
A future subject to explore involves pregnancy in transplant recipients, which is reported more frequent nowadays due to a larger younger population that have received this procedure, considering that bone loss might be found in the females of reproductive age (although we have identified no such cases of PAO so far) [102].
In our analysis, we did not include young females with already known causes of fractures such as osteogenesis imperfecta, multiple myeloma, primary hyperparathyroidism, major beta-thalassemia, or glucocorticoid osteoporosis for whom the diagnostic of PAO/LAO is most probably inadequate [103][104][105][106][107]. To the best of our current knowledge, physiological bone loss during late gestation and lactation might decrease the cutoff for fragility fractures in subjects that already have reduced BMD, but PAO/LAO remains distinct from this specific scenario [108]. Of note, Cushing's syndrome-associated osteoporosis during pregnancy represents an exceptional event that may mimic PAO/LAO [109].
Traumatic or iatrogenic (including surgical of different types) injuries in pregnancy should also be differentiated from PAO [110][111][112]. Furthermore, persistent pain at the level of the pelvis after delivery is experienced in one out of six females, and MRI scanning might identify a bone fracture in a very small percent of these in addition to muscle injuries of various kinds [113]. Differential diagnosis of local pain is essential to avoid delaying the fracture identification and decision making to ensure infant care. A survey study involving 69 subjects (members of a social media group of patients who experienced PAO) from 12 countries showed an unexpectedly low rate of 4.4% receiving PAO confirmation within 4 weeks of the local pain starting. TPT was the most used anti-osteoporosis drug, and 6 months after the onset of the fracture-associated pain only 42% of them were able to provide childcare by themselves [43]. Typically, hip (or even lumbar) pain in pregnancy is due to weight gain. In 2021, a novel case of hip avascular necrosis was reported in pregnancy, and the associated pain also might mimic LOA (fewer than 100 cases have been reported so far, according to Mouchantaf et al.) [114]. Another exceptional differential diagnostic concerning back pain involves pregnancy-associated breast cancer metastasis [115]. Postpartum lower abdominal pain might also be caused by chronic symphysitis [116] ( Figure 2). ning might identify a bone fracture in a very small percent of these in addition to muscle injuries of various kinds [113]. Differential diagnosis of local pain is essential to avoid delaying the fracture identification and decision making to ensure infant care. A survey study involving 69 subjects (members of a social media group of patients who experienced PAO) from 12 countries showed an unexpectedly low rate of 4.4% receiving PAO confirmation within 4 weeks of the local pain starting. TPT was the most used anti-osteoporosis drug, and 6 months after the onset of the fracture-associated pain only 42% of them were able to provide childcare by themselves [43]. Typically, hip (or even lumbar) pain in pregnancy is due to weight gain. In 2021, a novel case of hip avascular necrosis was reported in pregnancy, and the associated pain also might mimic LOA (fewer than 100 cases have been reported so far, according to Mouchantaf et al.) [114]. Another exceptional differential diagnostic concerning back pain involves pregnancy-associated breast cancer metastasis [115]. Postpartum lower abdominal pain might also be caused by chronic symphysitis [116] (Figure 2).

Gap 5: Is There a Place for COVID-19 Pandemic Considerations?
Our research mainly streams the second and third year of the COVID-19 pandemic, whereas medical realities continued to gain attention with the identification ofnew conditions or new approaches to diseases due to the infection itself or social and medical adjustments; overall, all medical and surgical fields have produced dynamic data [117][118][119][120]. Regarding the particular domain of bone changes (including during pregnancy and lactation), reductions in outdoor activities and sun exposure, deficiencies in applying pre-pandemic protocols of serial check-up, chronic stress and anxiety, as well as direct skeletal effects ongoing through coronavirus infection are parameters to be taken into consideration, as seen in the general population [121][122][123]. The infection has not been

Gap 5: Is There a Place for COVID-19 Pandemic Considerations?
Our research mainly streams the second and third year of the COVID-19 pandemic, whereas medical realities continued to gain attention with the identification ofnew conditions or new approaches to diseases due to the infection itself or social and medical adjustments; overall, all medical and surgical fields have produced dynamic data [117][118][119][120]. Regarding the particular domain of bone changes (including during pregnancy and lactation), reductions in outdoor activities and sun exposure, deficiencies in applying pre-pandemic protocols of serial check-up, chronic stress and anxiety, as well as direct skeletal effects ongoing through coronavirus infection are parameters to be taken into consideration, as seen in the general population [121][122][123]. The infection has not been listed as a potential contributor to PAO/LAO, but two other aspects are reported: one is the decision to perform an X-ray scan in order to confirm PAO during late pregnancy, since MRI scanning was not available due to strict regulations, with a good maternal-fetal outcomes [56]. The second aspect is reflected in the report of a 20-kg weight gain due to self-quarantine in a 40-week pregnant female who experienced an SSF that responded well to a conservative approach [73]. Further data will point out the true lessons we need to learn from this stage of the pandemic era.

Gap 6: Multidisciplinary Tools to Diagnose PAO/LAO
Clinical suspicion is not enough for a clear diagnosis in most cases of PAO/LAO, but the condition should not be dismissed based on its rarity, because of potential severe consequences that we have mentioned. MRI remains the gold standard for identifying fractures in pregnant females. MRI is allowed during the second and third trimesters, and a case-by-case decision should be made during the first trimester [124,125]. Despite not being a practical alternative, we mention the case reported by Klimko et al. [56] that used X-ray in week 35 (under special circumstances) and no fetal risk was registered [56].
A new method (as yet without a current standardized approach) might be represented by the use of blood and/or urinary BTMs. In cases where these are very high, they could be helpful to indicate PAO/LAO in patients with spontaneous fractures, or they should be considered during treatment against osteoporosis [126]. This approach was used amid the COVID-19 pandemic in patients with osteoporosis and associated fractures that were not able to receive medical care in person due to regulations [127]. Lampropoulou-Adamidou et al. [45] pointed out that blood P1NP levels after 4 weeks of starting TPT represent a surrogate marker for predicting the response to the drug by being positively correlated with DXA-BMD after 1 year, as similarly seen in menopausal osteoporosis [45,128,129].
DXA is used only after delivery. We identified two main types of DXA results in LAO: those with normal BMD and low BMD/Z-score. A normal DXA result does not exclude diagnosis when fractures are confirmed and have no alternative cause such as trauma or secondary osteoporosis. However, a normal BMD at periodical check-up is not particularly helpful for patients under specific medication deciding to stop it (and here the use of BTMs might find its place). Some explanations for a normal DXA report might be a high BMI (which is not the norm), an anomoly of microarchitecture rather than BMD, lack of standardization in DXA assessment in the target reference population, local bone loss due to immobilization rather than a general process as found, for instance, in one study where more than two-thirds of subjects with SSFs had normal BMD [71,130,131]. However, a low BMD is generally expected; previous reports showed a mean DXA Z-score of −3.2 SD (lowest value of −7.8 SD) [74]. We found Z-score values varying from −2.2 SD to −4 SD [23,44,51,59,60,62,65].
TBS has been used for exploring bone microarchitecture. No standard TBS interpretation in this population is reported, as opposed to published data on menopausal populations, especially type 2 diabetic females [131]. Moreover, data have shown that grand multiparity is associated with low TBS in the menopause [132]. The use of highresolution peripheral quantitative CT rather than TBS might support this type of skeleton damage [47,48,58].
Collaterally, we mention that PAO/LAO-induced radiculopathy requires a neurologic evaluation, stressing the importance of having a multidisciplinary team in such cases [71]. 4.7. Gap 7: From "Old" to "New" Therapies for PAO/LAO Typically, PAO/LAO is self-limited, but its devastating effects such as hip fracture or serial VFs might have a dramatic impact. Once recognized, it is difficult to decide on a drugfree option for patients from the perspective of specific medication against osteoporosis in addition to deciding the type and timing of orthopedic surgery. Due to the rarity of the condition, a team of surgeons and other practitioners should make the decision for hip surgery per primam (or with respect to delivery in PAO) or in cases with an expected poor outcome under medication.
We observed a dominance of "new" approaches, namely TPT as opposed to prior use of BPs [40,45,46,48,62]. The first use of ROM was reported in a case that was non-responsive to TPT, thus escalating a new alternative line of medication [60]. BPs are used less because they accumulate in bone, but DEN, TPT, and calcitonin display lesser long-term effects so should be considered first [40,45,46,48,62,66]. However, for instance, murine experiments showed that transient use of alendronate during pregnancy and lactation might not be harmful for the newborn [133].
Different studies showed a good response and safety profile with regard to TPT in women with premenopausal osteoporosis [134,135]. To our knowledge, three main types of TPT-associated issues remain to be addressed in future: for how long we should treat with TPT; whether sequence therapy (as known from menopausal osteoporosis) is actually necessary; and for how long a consecutive pregnancy (if planned) should be postponed. According to analyzed data, TPT was prescribed from 6 to 24 months (20 µg/day) and a second gestation should be at least 2-3 years after starting TPT [40,45,46,48,62]. Lee et al. [46] revealed that similar results in TPT discontinuation versus a sequential approach were achieved within a 3-year time frame [46]. Hadji et al. [40] also showed that no BPs or DEN are necessary following TPT in order to preserve BMD achieved through TPT exposure, despite the fact that TPT candidates have a more severe osteoporosis profile in terms of multiple VFs [40]. Lampropoulou-Adamidou et al. [46] confirmed that TPT-related BMD gain (mostly lumbar) is higher than with the standard approach using vitamin D and calcium, thus it should be chosen for those patients with a high fracture risk [46].
Notably, PAO remains one potential indication for a non-obstetric cause-related cesarean section and a decision should be carefully taken [136].
The profile of high fracture risk in PAO/LAO remains an open issue, but we consider that the number of VFs and their clinical impact on the individual are important, in addition to other contributors that we mentioned and which should be taken into account. In the absence of standard risk calculators, a multidisciplinary decision is required in each case. The limits of the current analysis derive from the low level of statistical evidence, the difficulty of approaching such a topic using large randomized trials, variations in the data reported for different cases, the lack of standard protocols, and off-label use of certain anti-osteoporotic drugs ( Figure 3).  . Algorithm for approaching PAO/LAO: starting with local pain due to fractures, the panel of investigation depends on pre-delivery or post-delivery status and is followed by the decision about therapy including standard calcium and vitamin D, surgery (if needed), and medication (in cases with a high fracture risk when considering the potential contributors). Gene testing, particurarly for LRP5, WNT1, and COL1A1/A2 genes should be considered in severe cases, probably to help the selection of teriparatide candidates (please see references within main text). Abbreviations: MRI = magnetic resonance imaging; BTM = bone turnover markers; DXA = dual-energy X-ray absorptiometry; TBS = trabecular bone score; HRPQCT = high-resolution peripheral quantitative computed tomography; TPT = teriparatide; DEN = denosumab; BPs = bisphosphonates.

Conclusions
PAO/LAO remains a fascinating and challenging condition that requires considering maternal-fetal outcomes and taking care of the offspring, and it is a task for a multidisciplinary team, since a standardized approach is lacking. Personalized medicine rep- Figure 3. Algorithm for approaching PAO/LAO: starting with local pain due to fractures, the panel of investigation depends on pre-delivery or post-delivery status and is followed by the decision about therapy including standard calcium and vitamin D, surgery (if needed), and medication (in cases with a high fracture risk when considering the potential contributors). Gene testing, particurarly for LRP5, WNT1, and COL1A1/A2 genes should be considered in severe cases, probably to help the selection of teriparatide candidates (please see references within main text). Abbreviations: MRI = magnetic resonance imaging; BTM = bone turnover markers; DXA = dual-energy X-ray absorptiometry; TBS = trabecular bone score; HRPQCT = high-resolution peripheral quantitative computed tomography; TPT = teriparatide; DEN = denosumab; BPs = bisphosphonates.

Conclusions
PAO/LAO remains a fascinating and challenging condition that requires considering maternal-fetal outcomes and taking care of the offspring, and it is a task for a multidisciplinary team, since a standardized approach is lacking. Personalized medicine represents the basis of this approach. The importance of early diagnosis massively improves the prognosis for mother and her child in both the short and long term. While anti-osteoporotic drugs such as teriparatide or romosozumab might need further studies to be proved helpful and safe, orthopedic intervention from open surgery to conservative management is essential. Longitudinal studies, interventional trials, and larger databases to support genetic diagnosis might represent the next steps in this field.

Conflicts of Interest:
The authors declare no conflict of interest.